The invention relates to inhalation apparatus and methods suitable for administering oronasal medication. Further, the apparatus and methods are adapted to permit incentive spirometry with use of the inhalation apparatus.
Oronasal delivery of drugs has been known for some time and gained acceptance for various types of drugs. A metered dose of bronchodilators and steroids from a pressurized aerosol cannistor delivered through the mouth to deliver medicines into the air passageways for delivery to the lungs has become an important method for drug delivery. Despite the potential uses of this type of drug delivery system, patients generally have not made optimum use of the drug delivery devices of this type. Gayrard et al, "Mauvaise utilisation des aerosol-doseurs par les asthmatiques", Respiration, Vol. 40, pp. 47-52 (1980), reported that of physician-trained patients in a particular study, approximately half (48%) did not properly use their aerosol devices a month after having received instructions from their physician, while only slightly more than a quarter of those studied (28%) followed the manufacturer's recommendations. Heimer et al, "The Effect of Sequential Inhalations of Metaproterenol Aerosol in Asthma", J. Alleger. Clin. Immunol., Vol. 66, pp. 75-77 (1980), compared FEV.sub.1.0 in asthmatics after both a single dose and then three sequential doses of 5-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]benzene diol aerosol at intervals of ten minutes. The FEV.sub.1.0 was greater with the sequential administration, favoring the possibility that airways which were dilated by the initial dose of the brochodilator aerosol permitted the entry of greater aerosol in subsequent administrations. Riley et al, "Enhanced Responses to Aerosolized Bronchodilator Therapy in Asthma Using Respiratory Maneuvers", Chest, Vol. 76, pp. 501-507 (1979), studied the administration of 800 ug isoproterenol at 20 or 80% VC versus the administration of 4 doses of 200 ug every twenty (20) minutes to asthmatics. These studies confirmed the findings of Heimer et al, supra, that better bronchodilatation was achieved with sequential administration, and additionally reported that delivery at 80% VC produced more effective bronchodilatation than delivery at 20% VC. Riley et al related the latter finding to the facilitation of aerosol penetration by the greater mechanical opening of the airways at the high lung volume. Newman et al, "Simple Instruction for Using Pressurized Aerosol Bronchodilators", J. Roy. Soc. Med., Vol. 73, pp. 776-779 (1980), found that maximal bronchodilatation as judged by an increase in FEV.sub.1.0 was achieved when metered terbutaline aerosol 500 ug was employed with a slow, deep inhalation, 25 L/minute, followed by a 10 second breathholding. The lung volume at which the aerosol was inhaled had no effect on the degree of bronchodilatation. Rapid inhalation at 80 L/minute of terbutaline aerosol followed by 4 or 10 second breathholding was less effective than the slow inhalation delivery procedure.
The mass median aerodynamic diameter of commercial metered aerosol preparations is variable and depends upon the method of analysis. Hiller et al, "Simple Instruction for Using Pressurized Aerosol Bronchodilators", Am. Rev. Resp. Dis., Vol. 118, pp. 311-317 (1978), found that nine metered aerosols had a mass median aerodynamic diameter ranging from 2.8 to 4.3 um and a geometric standard deviation ranging from 1.5 to 2.1. Count median diameter was measured with "Spart", a single particle aerodynamic relaxation time analyzer, and the mass median aerodynamic diameter calculated. However, small errors in the estimation of the geometric standard deviation produce major changes in the calculation of the mass median aerodynamic diameter. Kim et al, "Aerodynamic Size Distribution of Metered-dose Aerosols in Low and High Humidity Conditions", Am. Rev. Resp. Eis., Abstract (in press), (1981), reported on measured mass median aerodynamic diameter of metered aerosols by sampling from a large reservoir container through a six-stage Anderson cascade impactor whose plates were coated with petroleum jelly to eliminate the bounce off of particles. Size distributions were approximately log normal and had a mass median aerodynamic diameter ranging from 3.3 to 5.5 um with a geometric standard deviation of 2.0 to 2.2. These diameters were 30 to 60% larger than reported by Hiller et al, supra, but this discrepancy can be reconciled by increasing the geometric standard deviation of these authors by 5 to 10%. For practical purposes, one can take 4 um mass median aerodynamic diameter as an average estimate of particle size delivered by metered aerosol containers.
Metered aerosols are delivered with such a high velocity that a significant fraction is lost to impaction on the tongue and oropharynx before ever reaching the airways. Absorption of adrenergic agonists through the oropharyngeal mucosa can bring about unwanted cardiac effects; deposition of insoluble corticosteroids in the mouth can promote oropharyngeal candidiasis. Impaction of suspension aerosols, e.g., Duo-medihaler, Medihaler-iso, Medihaler-epi, Alupent, in the oropharynx has generally been found to be less than liquid types, e.g., Bronkometer, Mistometer, Berotec. This has been measured with in vivo chemical or analysis of radioisotopically labelled compounds by rinsing the mouth and recovering the drug and with in vitro models through physical methods such as weighing or collection by impingement [Paterson et al, "Method of Using Pressurized Aerosols", Brit. Med. J., Vol. 1, pp 76-77 (1976); Bell et al, "Variation in Delivery of Isoprenaline From Various Pressurized Inhalers", J. Pharm. Pharmac. 25, Supp. 32, pp 36P (1973); Laros et al, "Absorption, Distribution and Excretion of the Tritium-labelled B.sub.2 Stimulator Fenoterol Hydrobromide Following Aerosol Administration Instillation Into the Bronchial Tree", Repiration, Vol. 34, pp. 131-140 (1977); Kim et al, "Delivery Efficiency of Metered-dose Aerosols by Usual Administration and Through a Reservoir Bag", Am. Rev. Resp. Dis., Abstract (in press) (1981)]. Values for loss of aerosol under these circumstance range from 43 to 57% for suspension aerosols and 53 to 90% for liquid aerosols [Paterson et al, supra; Bell et al, supra; Laros et al, supra]. As reported in "Delivery Efficiency of Metered-dose Aerosols by Usual Administration and Through a Reservoir Bag", we have fabricated a glass model of the adult oropharynx and delivered aerosol from several metered aerosols to its opening while a continuous flow of either 10 or 30 L/minute of dry and humid (90% R.H.) air was passed through it. Aerosol particles passing through the model were collected on a filter at its outlet and weighted with a microbalance. Deposition of suspension aerosols onto the oropharyngeal model using dry air flowing at 30 L/minute ranged from 44 to 54% of administered dose and for liquid aerosols 62 to 69%. These values increased 5 to 15% when the flow rate was decreased from 30 to 10 L/minute at the same humidity or when air with 90% R.H. was employed.
Auxilliary delivery devices are discussed by Lindgren et al, Lindgren et al, "Improved aerosol therapy of asthma: effect of actuator tube size on drug availability", Eur. J. Respir. Dis., Vol. 61, pp. 56-61 (1980), who compared metered terbutaline aerosol alone and in combination with two differently shaped tubes: (a) a straight glass tube (ST) of 100 mm length with an internal diamter of 32 mm (80 ml volume) and a pear-shaped glass tube (PT) of 250 mm length with maximal internal diameter of 130 mm (1000 ml volume). Lindgren et al measured FEV.sub.1.0 in asthmatics after sequential inhalations of terbutaline at 25 minute intervals. All methods of administration produced an increase in FEV.sub.1.0 but greater and more prolonged duration of action was observed with the PT. The Lindgren et al disclosure is representative of auxiliary delivery devices that have been introduced in conjunction with metered aerosols to obviate the incorrect usage of delivery systems device common to the prior art and to minimize impaction loss onto the oropharyngeal mucosa. The spacer tube also produced a more effective bronchodilation than metered aerosol alone. In these types of auxilliary delivery devices, the aerosols impact on the walls of the tube rather than on the oropharynx. In another patient study reported by Bloomfield et al, "A Tube Spacer to Improve Inhalation of Drugs From Pressurised Aerosols", Brit. Med. J., Vol. 2, p. 1479 (1979), the spacer tube did not produce a greater increase of FEV.sub.1.0 compared to metered aerosol when a correct usage of both of the devices was employed.
Apparatus for administering drugs to pulmonary tissue are known in the prior art. Conventional apparatus for administering such drugs are shown, for instance, in U.S. Pat. No. 4,174,712 and other references known to those skilled in the art. These apparatuses have in common a pressurized inhaler bottle containing an aerosol propellent and a medication to be applied to the pulmonary tissue. A nebulizer is associated with the pressurized inhaler bottle whereby the actuation of the combination nebulizer-pressurized inhaler bottle introduces a predetermined dosage of medication to the oronasal cavity area of a patient.
Difficulties with administering this type of medication have been experienced in using the prior art devices. For instance, it is found that direct spraying of the medicant into the oral cavity leaves a substantial portion of the dosage on the patient's tongue and otherwise not in the pulmonary tissue where the drug is required. This particularly poses a problem for steroidal inhalants which have strict limits on total dosage, and on side effects such as promoting fungile growth on the tongue. Further, some patients have difficulty in effecting the inhalation of the medication. The resulting process of delivering the drugs to the pulmonary tissue results in only a portion of the required dosage reaching the tissue area. This requires repeated dosages to be given to the patient so that sufficient medication reaches the pulmonary tissue. In addition, a portion of the inhaled medication is not absorbed, thus it is lost upon expiration. Repeating the dosage also places an unnecessary amount of propellant contained in the pressurized aerosol mist into the respiratory system than is otherwise desired. The processes and apparatus of the prior art therefore do not provide a uniform distribution of pulmonary medication in the respiratory tracts. A further difficulty resulting from these prior techniques is that the rate of distribution of the pulmonary medication is not constant from patient to patient or dosage to dosage.
Conventional inhalers require a simultaneous actuation of a nebulizer and aerosol container with the act of inhalation. This degree of coordination required for use of these devices makes it difficult to administer pulmonary medication to young children and patients unfamiliar with the technique. Further, it has been found that a long and slow inspiration period promotes an efficient distribution of medication to partially occluded airways. The conventional inhalers are not adapted to a long and slow inspiration period as actuation and inhalation steps are conducted simultaneously, often creating a bolus of concentrated medication in the inhaled air.
The prior art incentive spirometer has as a rule been a complicated mechanism offering some difficulty to patients to operate. Further, spirometer technology has been directed to volumetric measurements of the inspiration of a patient. Efforts to simplify spirometer technology are exemplified in our U.S. Pat. No. 4,327,741, granted May 4, 1982, hereby incorporated by reference. Incentive spirometers for conducting therapeutic and prophylactic respiratory maneuvers are described in this reference. These devices, however, do not provide during use a negative thoracic pressure for inhibiting a rapid inhalation. By inhibiting the rapid inhalation, certain therapeutic benefits are realized in an incentive spirometer not attainable in these prior art devices.
As in the case in the inhalation devices, incentive spirometers are desired which encourage a long and slow inspiration period. During respiratory maneuvers, it is advantageous to provide a visual or audible means for a patient to gauge the breathing progress. Some prior art devices are flow controlled, whereby the flow of air is monitored by the device. These devices, however, encourage a rapid inspiratory rate rather than a long, slow inspiration period. Other apparatus detect the volume of air respiration achieved and are in many instances cumbersome and complicated. Typically, they may comprise a calibrated bellows on a flat surface such as a bedside table and are interfaced to the patient with a long flexible hose. These devices have as a final goal a certain volume inspired. There is no direct feedback to the patient as to his progress during breathing until the final volume is achieved.
Furthermore, most of the prior art devices are not capable of providing a dosage of medication while conducting therapeutic maneuvers. The combination of an incentive spirometer with a medicinal inhaler is most promising in treating postoperative atelectasis and for clearing the small airways of the lungs.